Multicenter phase II study of Apatinib in non-triple-negative metastatic breast cancer

BMC Cancer

Hao Yu⁷  Xiaoyu Chen⁶  Biyun Wang⁶  Zhonghua Wang⁶  Jin Li⁶  Shusen Wang¹  Zhongsheng Tong²  Li Cai⁵  Yueyin Pan³  Changping Wu⁴  Wenwei Hu⁴  Jun Cao⁶  Xichun Hu⁶ 

[1]Sun Yat-Sen University Cancer Center, Guangzhou, China

[2]Tianjin Medical University Cancer Institute & Hospital, Tianjin, China

[3]The First Affiliated Hospital of Anhui Medical University, Hefei, China

[4]The Third Affiliated Hospital of Suzhou University, Suzhou, China

[5]The Third Affiliated Hospital of Harbin Medical University, Harbin, China

[6]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

[7]Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China

关键词: VEGF;    Metastatic breast cancer;    Apatinib;   

Others  :  1120225
DOI  :  10.1186/1471-2407-14-820

 received in 2013-08-14, accepted in 2014-10-27,  发布年份 2014

【 摘 要 】

Background

Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease.

Methods

This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle.

Results

38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m – 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m – 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization.

Conclusions

Apatinib exhibited objective efficacy in heavily pretreated, metastatic non-triple-negative breast cancer with manageable toxicity, and it might be better to be tested in breast cancer with high angiogenesis dependency.

Trial registration

ClinicalTrials.gov: NCT01653561.

【 授权许可】

   
2014 Hu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Althuis MD, Dozier JD, Anderson WF, Devesa SS, Brinton LA: Global trends in breast cancer incidence and mortality 1973–1997. Int J Epidemiol 2005, 34(2):405-412. Epub 2005 Feb 28
• [2]Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005, 365(9472):1687-1717.
• [3]Banerjee S, Dowsett M, Ashworth A, Martin LA: Mechanisms of disease: angiogenesis and the management of breast cancer. Nat Clin Pract Oncol 2007, 4:536-550.
• [4]Ferrara N: Vascular endothelial growth factor basic science and clinical progress. Endocr Rev 2004, 25:581-611.
• [5]Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010, 28:3239-3247.
• [6]Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007, 357:2666-2676.
• [7]Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J: RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor r 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011, 29:1252-1260.
• [8]Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS: RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2011, 29(32):4286-4293. Epub 2011 Oct 11
• [9]Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355(24):2542-2550.
• [10]Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N: AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007, 370(9605):2103-2111.
• [11]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350(23):2335-2342.
• [12]Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX, Gynecologic Oncology Group: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011, 365(26):2473-2483.
• [13]Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascularendothelial growth factor and platelet-derived growth factor receptors: determination of apharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 2003, 9(1):327-337.
• [14]Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006, 5(10):835-844.
• [15]Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, Siena S, Laferriere N, Peña C, Lathia C, Bergamini L, Gianni L: Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs 2009, 20:616-624.
• [16]Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M, Flynn PJ, Fitch TR, Perez EA: Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol 2009, 27(1):11-5. Epub 2008 Dec 1
• [17]Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD: Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008, 26:1810-1816.
• [18]Li J, Zhao X, Chen L, Guo H, Lv F, Jia K, Yv K, Wang F, Li C, Qian J, Zheng C, Zuo Y: Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer 2010, 10:529. BioMed Central Full Text
• [19]Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, Cheng Y, Wang Z, Zheng L, Tao M, Zhu X, Ji D, Liu X, Yu H: Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 2013, 31(26):3219-3225.
• [20]Hu X, Zhang J, Xu B, Jiang Z, Ragaz J, Tong Z, Zhang Q, Wang X, Feng J, Pang D, Fan M, Li J, Wang B, Wang Z, Zhang Q, Sun S, Liao C: Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer. Int J Cancer 2014. Epub ahead of print
• [21]Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356(2):125-134.
• [22]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359(4):378-390.
• [23]Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A: A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003, 30(5 Suppl 16):117-124.
• [24]Baselga J, Segalla JG, Roché H, Del Giglio A, Pinczowski H, Ciruelos EM, Filho SC, Gómez P, Van Eyll B, Bermejo B, Llombart A, Garicochea B, Durán MÁ, Hoff PM, Espié M, de Moraes AA, Ribeiro RA, Mathias C, Gil Gil M, Ojeda B, Morales J, Kwon Ro S, Li S, Costa F: Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol 2012, 30:1484-1491.
• [25]Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, Kaklamani V, Stepanski EJ, Rugo HS, Wang W, Bell-McGuinn K, Kirshner JJ, Eisenberg P, Emanuelson R, Keaton M, Levine E, Medgyesy DC, Qamar R, Starr A, Ro SK, Lokker NA, Hudis CA: Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negativeadvanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res 2013, 19(10):2745-2754.
• [26]Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, Jain M, Ro SK, Lokker NA, Schwartzberg L: A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer 2013, 49:312-322.
• [27]Mariani G, Burdaeva O, Roman L, Staroslawska E, Udovitsa D, Driol P, Goisis G, Zamagni C, Semiglazov V, Gianni L: A double-blind, randomized phase IIb study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with docetaxel and/or letrozole in patients with metastatic breast cancer (MDC): FM-B07-01 Trial [abstract]. Eur J Cancer 2011, 47(Suppl 2):10.
• [28]Rugo HS, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A, Liau KF, Kim S, Bycott P, Rosbrook B, Bair AH, Soulieres D: Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol 2011, 29(18):2459-2465.
• [29]Tang JR, Markham NE, Lin YJ, McMurtry IF, Maxey A, Kinsella JP, Abman SH: Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol 2004, 287(2):L344-51.